We request funding to support/strengthen an ongoing collaboration in basic biomedical research in the area of genetics of osteoporosis between the US-based and NIH-supported PI at University of Missouri-Kansas City (UMKC) and young scientists in Xi'an Jiaotong University (XJTU), China. The collaboration, spanning over the past 4 years and supported mainly by funding from China, has resulted in >20 publications in the field of osteoporosis, seeded promising research careers for several young scientists in China, and established platforms for genotyping, phenotyping, gene expression profiling and high performance computing for genetic studies of osteoporosis and other human complex diseases. Funding of this application will support continuation of this productive working relationship, which is essential to the development of basic medical research of osteoporosis in China, and accelerate career development of the young Chinese collaborators. If this application is funded, a match-up fund will be granted from the collaborating institution, XJTU, to serve as additional support for the proposed collaborative project in this proposal (Appendix z). Osteoporosis is a major public health problem, mainly characterized by low bone mineral density (BMD) and high susceptibility to osteoporotic fractures (OF). With the aging of the world population, the mortality and morbidity associated with OF places an increasingly heavy burden on modern societies in the west as well the east. So far, extensive efforts have been made to identify genes associated with BMD, with few studies directly examining OF as the study phenotype. However, OF is the devastating outcome of osteoporosis and studies showed that genes significant for BMD may not all be relevant to OF. Therefore, disclosing the genetic factors influencing BMD, which are also important to OF, should be of greater significance for understanding the pathogenesis of osteoporosis. Through various genetic and genomic approaches, we identified 2 prominent candidate genes (RANK and CYP19) significant for hip BMD in Caucasians. However, their significance to Chinese in terms of BMD and/or OF is unknown. In this study, our HYPOTHESIS is that genes significant for hip BMD in Caucasians are also associated with hip BMD and hip osteoporotic fractures (HF) in Chinese. The GOAL is to identify the genes for hip BMD and HF in Chinese by testing in Chinese the significance of the genes associated with hip BMD in Caucasians. Our Specific Aims are 1) To test association with hip BMD and HF in Chinese population of two genes, RANK and CYP19, which were associated with hip BMD in Caucasians;2) To select another six osteoporosis candidate genes to be identified from our parent projects and test their association with hip BMD and OF in the Chinese population. This project will contribute to better understanding the genetic basis of osteoporosis in Chinese. The genes identified significant for hip BMD and HF in Chinese may serve as markers/targets for genotype-based prevention and intervention to reduce the incidence of HF. As an international support for the PI's collaboration with XJTU, this project will provide a unique opportunity to enhance the research experience and capability of the collaborating young scientists in China, to accelerate their transition into independent investigators, and to help advance the overall level of basic scientific research of osteoporosis in China. Together with the ongoing studies in Caucasians, this project will provide novel insights into the ethnic specificity and/or generality of the genetic basis of osteoporosis for the two major ethnic populations in the world, thus contribute to addressing the global problem of osteoporosis. PERFORMANCE SITE(S) (organization, city, state) University of Missouri- Kansas City (UMKC), Kansas City, Missouri, USA Xi'an Jiaotong University (XJTU), Xi'an, Shaanxi Province, P.R. China Yale University, New Heaven, CT, USA University of Connecticut, Farmington, CT, USA PHS 398 (Rev. 04/06) PUBLIC HEALTH RELEVANCE: Osteoporosis is a disease mainly characterized by low bone mineral density (BMD), predisposing a person to an increased risk of osteoporotic fracture (OF). OF at hip is the most devastating outcome of osteoporosis. Though extensive efforts have been made to identify genes underlying osteoporosis, most of the genetic studies were focused on its surrogate phenotype BMD, and few studies directly study OF per se as the phenotype for osteoporosis. The goal of this project is to identify the genes not only for BMD but also for OF in Chinese, by testing in a large Chinese sample the osteoporosis candidate genes identified in Caucasians. This project will contribute to better understanding the genetic basis of osteoporosis in Chinese. The results will provide novel insights into the ethnic specificity and/or generality of the genetic determination of osteoporosis for the two major ethnic populations, i.e., Caucasians and Chinese, thus contribute to addressing this global health problem. The genes identified may serve as targets for genotype-specific interventions to reduce the incidence of OF, and eventually improve the control of osteoporosis pandemic and enhance people's health in China. PHS 398 (Rev. 04/06)